THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



More research needed to determine gender factor in pain

Pain is a common symptom for many rheumatic diseases, and it affects women disproportionally. But the role that gender differences play in pain has not been considered nearly enough.

GenderDifferences
Jon Levine, MD, PhD

That’s the conclusion of Jon Levine, MD, PhD, who presented the ACR’s State-of-the-Art Lecture Gender Differences in Pain Mechanisms on Sunday afternoon.

“It certainly has been an area that has been understudied for many years. We have actually in many ways made very little progress,” said Dr. Levine, Professor of Medicine in the Divisions of Rheumatology, Clinical Pharmacology, and Experimental Therapeutics as well as a member of the graduate program in neuroscience at the University of California, San Francisco.

He argued that it was wrong to assume that just because pain might manifest itself similarly in men and women that the pain mechanisms are the same. Part of the problem in dealing with this issue, Dr. Levine said, is that there is not even a consensus on the definition of chronic pain.

The pathways that signal pain in males and females are different, he said, and research shows that sex hormones play a role. Estrogen is a key. If you take a gonadectomized female animal, her signaling mechanism will be the same as in a male. Reintroducing estrogen re-regulates her pathway. Outcomes are different in gonadectomized males.

Dr. Levine also addressed analgesia, which is largely regulated by the descending pain control pathway, a classic pain-relief mechanism in the body.

There are drugs that work with the mu and kappa classes of opioid receptors. Drugs targeted at the kappa receptors include nalbuphine, butorphanol, and pentazocine. If you give those drugs to women, Dr. Levine said, they produce pain relief at least as good, if not better, than morphine. If you give them to men, after small amount of pain relief, it actually makes their pain much worse.

It turns out that the kappa opioids are actually working at two different receptors, one that makes pain better, and one that makes pain worse. Dr. Levine said men have more receptors that make pain worse.

The question of whether or not there are sex differences has blindsided some clinicians. Some clinicians, Dr. Levine said, refuse to consider there are sex differences in pain or analgesia.
“If you don’t look, you don’t see,” he said.

One study that Dr. Levine co-authored concluded that there are gender differences in protein kinase C, protein kinase A, and nitric oxide signaling to epinephrine-induced hyperalgesia. The results suggest that these differences are estrogen-dependent and are regulated at the level of the β-adrenergic receptor or coupling of the receptor to heterotrimeric G-proteins.

Dr. Levine also participated in a study looking at k-opioid agonism. The study compared two k-opioid analgesics, nalbuphine and butorphanol, in males and females who underwent surgery for the removal of third molar teeth.

The researchers found that both nalbuphine and butorphanol produced significantly greater analgesia in females as compared with males. The published paper concluded that k-opioid analgesia is greater in females than in males, probably reflecting a difference in k-opioid-activated endogenous pain modulating circuits.